This translational project will develop a novel framework to optimize the dosing of seizure therapies for the treatment of medication resistant disorders. Despite advances in antidepressant interventions, none has replaced electroconvulsive therapy (ECT) in its acute efficacy and spectrum of action. However, ECT carries the risk of significant cognitive side effects, some of which are lasting. Major improvements in the risk/benefit ratio of ECT have been made over the past few decades, including the introduction of more focal stimulation with magnetic seizure therapy (MST), yet our knowledge of the optimal dosing of seizure therapies remains relatively rudimentary. Lacking an understanding of the biophysical and physiological mechanisms, refinements in ECT/MST technique must rely exclusively on time-consuming and costly clinical trials. Consequently, key questions remain unanswered, such as: (1) how to position the electrode or coil to TARGET stimulation to specific brain areas, (2) how best to INDIVIDUALIZE the dosage for each patient, and (3) how to OPTIMIZE stimulus parameters for efficient seizure induction. Answers to these questions could lead to substantial advances in the tolerability of the treatment and would inform clinical decision-making. Addressing this knowledge gap, we propose a new platform for the rational dosing of electric and magnetic seizure therapy that couples computational modeling with empirical validation to inform the targeting, individualization, and optimization of ECT/MST technique. This 5-year collaborative project spanning the disciplines of engineering and psychiatry entails two interrelated lines of work: computational modeling, and in vivo testing to physiologically calibrate the model and empirically determine the dynamic interaction between pulse train characteristics and seizure initiation. This proposal has 3 aims: (AIM 1) to inform TARGETING, we will simulate the strength and focality of neural stimulation as a function of ECT electrode and MST coil configuration using realistic head models calibrated through empirical neural threshold measurement in vivo; (AIM 2) to guide the INDIVIDUALIZATION of dosage, we will titrate pulse amplitude for efficient seizure induction in vivo and evaluate it as a means of controlling the focality of stimulation; and (AIM 3) to OPTIMIZE train parameters, we will empirically determine the most efficient frequency and directionality of pulse trains for seizure induction. This approach accounts for tissue conductivity and the anisotropy of white matter as measured by diffusion tensor imaging, it includes physiological calibration of field maps relative to neural activation thresholds, and it evaluates relatively ignored parameters which are central to controlling the focality and physiological action of seizure therapies. Pilot data supporting each of the aims demonstrate that lowering pulse amplitude improves focality and seizure induction is more efficient with lower frequencies and unidirectional pulse trains. This work provides a basis for rational dosing of seizure therapies that could help improve their risk/benefit ratio and guide the development of safer alternatives for severely ill patients. PUBLIC HEALTH RELEVANCE: Clinical depression affects upwards of 34 million US citizens, but only about one third of those are effectively treated with medications. For the remainder, electroconvulsive therapy (ECT) is an effective option but it carries a risk of side effects. This project couples state-of-the-art engineering methods with the latest developments in clinical psychiatry to inform the dosing of existing and novel seizure therapies so that persons with severe depression and other disabling disorders will have more effective and safer treatment options.